The major goal of this proposal is to further define the genetic contribution to the immunopathogenesis of insulin-dependent diabetes mellitus in NOD mice. Experiments are proposed to test the hypothesis that the NOD I-A locus with or without novel T cell receptor genes is necessary for the development of T cell specificities involved in disease. We will also determine if homozygosity for the NOD I-A locus required for disease and the mechanism by which the introduction of unrelated I-A genes prevents the development of disease. Experiments will initially be performed to confirm that the major histocompatibility complex (MHC) of NOD mice rather than another closely linked locus is involved in the development of insulitis. This will be accomplished by correlating insulitis and MHC genotype in various backcross combinations. Similar analyses will determine if NOD T cell receptor alpha- or beta- chain gene complexes contribute in a recessive or dominant manner to the pathogenesis of disease. The requirement for homozygosity of the NOD MHC in the development of insulitis will be determined in genetic backcrosses involving different non- NOD H-2 haplotypes that have similarities with that of the NOD. If a particular MHC allows for disease in heterozygous backcross mice, the possibility that it supplants the need for the NOD MHC will be tested by further inbreeding. In backcrosses where homozygosity is required, experiments are designed to test whether (1) peripheral expression of NOD I-A antigens correlates with the ability of a non-NOD MHC to suppresses disease and (2) whether the prevention of disease occurs at the level of the thymus. The latter studies will involve transplanting NOD vs. F1 thymus grafts into NOD mice that had previously been thymectomized, lethally irradiated, and reconstituted with T cell- depleted bone marrow. Finally, experiments are proposed to test whether the NOD MHC (plus or minus NOD T cell receptor gene complexes) is sufficient for the development of T cells that can mediate disease or whether other NOD gene loci are also required. This will involve the breeding of mice (B10 background) congenic for the NOD MHC (B10.NOD mice) and possibly mice congenic for a particular NOD T cell receptor gene complex. T cells from these congenic mice will be compared with those from NOD mice in the ability to transfer disease to T cell-depleted NOD or to irradiated B10.NOD recipients.